Dynamic sugars: Sweet approach to behaviour

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  • Published: Oct 1, 2014
  • Author: David Bradley
  • Channels: NMR Knowledge Base
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Exploration of Conformational Spaces of High-Mannose-Type Oligosaccharides by an NMR-Validated Simulation Credit: Koichi Kato

The dynamic behaviour of complicated sugar chains in solution has been followed at atomic resolution using a combination of a sophisticated nuclear magnetic resonance spectroscopic technique and a novel molecular dynamics simulation technique.

Tracing the dynamics of rapidly changing structures, particularly complex biomolecules, on the nanoscale is a difficult task, made somewhat easier by the recent work of Koichi Kato of the Institute for Molecular Science and Okazaki Institute for Integrative Bioscience in Okazaki, Japan. Writing in the journal Angewandte Chemie in September Kato and colleagues, Takumi Yamaguchi, Yoshitake Sakae, Ying Zhang, Sayoko Yamamoto and Yuko Okamoto, describe how they have developed a new approach to molecular dynamics that allows them to obtain a quantitative description of complicated sugar chains in solution at atomic resolution. The sugar chains studied are flexible auxiliaries found on the surface of proteins and so an important component of many avenues of biomedical and medicinal chemistry research.


The team explains how these sugar chains commonly mediate the way in which specific proteins communicate and so interact with other protein molecules, thus often deciding the fate of the protein. Examples of this process in action are commonly linked to infection and disease progression. For instance, sugar chains might lead to the modification of fatty lipids on the surface of our cells that opens them up, via acceptor sites, to viral infection. They may also be involved in causing conformational changes in cell proteins that lead to neurodegenerative problems, such as Alzheimer's disease. Kato and colleagues therefore recognize the importance of improving our understanding of these sugar codes and how they affect biological mechanisms at the molecular level. Ultimately, insights could lead to new targets for pharmaceutical intervention in a wide range of diseases.

Conformational studies are often stymied by the fast-moving nature of proteins and any associated moieties including sugar chains. Many experimental scientists and theorists have approached this challenge and NMR spectroscopy has repeatedly emerged as an informative tool for the task. It can, of course, determine the geometry of the sugar chains but only if the rapid motion of these groups can somehow be frozen, otherwise, the spectra provide averaged information over the conformational space that might not yield the detail researchers need. In contrast, molecular dynamics simulations can provide a theoretical perspective frame-by-frame. Kato's team thus reasoned that if these two techniques could be combined, then they might work synergistically with the spectra validating the simulation and the simulations allowing details to be teased apart from the averaged spectra.

High-field targets

They have now used high-field NMR spectrometers with stable isotope- and lanthanide-assisted techniques and the supercomputer facility operated by the Institute for Molecular Science for replica-exchange molecular dynamics (REMD) to capture distinct conformational snapshots of two very similar sugar chains in dynamic motion - high mannose oligosaccharides (M8B and M9). "The experimentally validated REMD simulation provided quantitative views of the dynamic conformational ensembles of the complicated, branched oligosaccharides, and indicated significant expansion of the conformational space upon removal of a terminal mannose residue during the functional glycan-processing pathway," the team reports.

Two critical breakthrough techniques were needed for this to be successful. First, the group employed genetically engineered yeast cells for production of homogeneous oligosaccharides in sufficient quantities for stable isotope labelling, a prerequisite of the detailed NMR work. Secondly, they used a paramagnetic probe at one end of the oligosaccharide molecules in order to obtain atomic-distance information. "This success enables a quantitative and highly sensitive characterization of minor but biologically relevant conformational species of sugar chains that will open the door for observing the dynamic behaviour of flexible biomolecules as potential drug targets," Kato explains.

"The next step of our research will be detailed characterization of dynamic carbohydrate-protein and even carbohydrate-carbohydrate interactions at the atomic level," Kato told SpectroscopyNOW. "Growing evidence indicates that clusters of sugar chains on cell surfaces offer a unique platform of assembly for proteins associated with neurodegenerative disorders. We hope that our approach opens the door to conformational studies of a variety of sugar chains and their clusters of biological and pathological interest."

Related Links

Angew Chem Int Edn, 2014, online: "Exploration of Conformational Spaces of High-Mannose-Type Oligosaccharides by an NMR-Validated Simulation"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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